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EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021
Abstract. Given their endemic prevalence in the past decades,
obesity and type 2 diabetes mellitus (T2DM) have become a
major sanitary burden with an important economic impact.
Novel treatment options have been designed with the aim
of reducing the numerous complications associated with
these metabolic disorders, as well as reducing morbidity and
mortality and improving the quality of life of those who suffer
from these disorders. Glucagon‑like peptide 1 receptor agonists
(GLP‑1 RAs) are among the most modern therapeutics that ta rget
‘diabesity’, a term used to describe the pathophysiological link
between obesity and T2DM. Their glucose‑lowering effects
are mainly attributed to glucose‑dependent insulin secretion,
glucagon inhibition and decreased gastric emptying. Given the
effects on the central nervous system, GLP‑1 RA usage may
lead to body weight reduction. GLP‑1 RAs are classied based
on their pharmacokinetic properties as short‑ and long‑acting
agents, with both types being administered by subcutaneous
injection. The latest agent from this drug class approved for
use in T2DM is semaglutide, a long‑acting compound that
is the only GLP‑1 RA available as an oral pill. The present
narrative review highlights the most recently published data
on the effects and safety of semaglutide in diabetic obesity,
also emphasizing its cardiovascular benets and potential side
effects. In addition, an overview of the role of semaglutide in
the treatment of non‑diabetic obesity is provided.
Contents
1. Introduction
2. GLP‑1‑biological effects and development of GLP‑1 RAs
3. Semaglutide in diabesity and non‑diabetic obesity
4. Semaglutide‑side effects and cautions
5. Future considerations
6. Conclusions
1. Introduction
Obesity is a metabolic disease with increasing prevalence
over the past decades, becoming an important economic and
health care burden (1). In 2016, the World Health Organization
estimated that worldwide more than 650 million adults
were obese (2). Obesity is associated with multiple chronic
comorbidities, being the leading risk factor for type 2 diabetes
mellitus (T2DM) (3).
The term ‘diabesity’ describes the pathophysiologic link
between obesity and T2DM and was first introduced by
Sims et al (4) in 1973. In 2019, the International Diabetes
Federation estimated that 463 million individuals world‑
wide have diabetes, projecting that by 2045, there will be
>700 million cases (5). The presence of ‘diabesity’ enhances
the risk of developing cardiovascular disease, thus increasing
morbidity and mortality (6,7). Managing diabesity is chal‑
lenging, consideri ng that numerous fre quently used antidiabetic
agents, such as sulfonylureas, meglitinides, thiazolidinediones
and insulin, may lead to weight gain and therefore cause a
vicious cycle (8).
One of the most modern drug classes available that is able to
achieve both glycemic control and weight loss are glucagon‑like
peptide 1 (GLP‑1) receptor agonists (GLP‑1 RAs). GLP‑1 RAs
are widely used as a glucose‑lowering therapy with weight
reduction and cardiovascular benets in T2DM, having also
beneficial effects in non‑diabetic obesity as a weight loss
Future perspectives in diabesity treatment: Semaglutide,
a glucagon‑like peptide 1 receptor agonist (Review)
MARIANA CORNELIA TILINCA1,2, ROBERT AURELIAN TIUCA3,4,
CRISTINA NICULAS5, ANDREEA VARGA6,7 and IOAN TILEA1,7
1Department of Internal Medicine, ‘George Emil Palade’ University of Medicine, Pharmacy, Science and Technology of
Targu Mures, 540142 Targu Mures; 2Compartment of Diabetology, Emergency Clinical County Hospital, 540136 Targu Mures;
3Department of Endocrinology, ‘George Emil Palade’ University of Medicine, Pharmacy, Science and Technology of
Targu Mures, 540142 Targu Mures; 4Department of Endocrinology, Mures County Clinical Hospital, 540139 Targu Mures;
5Richter Pharmacy 7, 400129 Cluj Napoca; 6Department of Family Medicine, ‘George Emil Palade’ University of Medicine,
Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures; 7Department of Cardiology II,
Emergency Clinical County Hospital, 540042 Targu Mures, Romania
Received May 5, 2021; Accepted July 27, 2021
DOI: 10.3892/etm.2021.10601
Correspondence to: Dr Robert Aurelian Tiuca, Department of
Endocrinology, Mures County Clinical Hospital, 38 Gheorghe
Marinescu Street, 540139 Targu Mures, Romania
E‑mail: tiuca.robert@gmail.com
Key words: semaglutide, glucagon‑like peptide 1, type 2 diabetes
mellitus, obesity, diabesity
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
2
adjuvant therapy (9,10). The present narrative review aimed
to highlight the effects of semaglutide, the most recently
approved GLP‑1 RA for T2DM as indicated in the existing
literature, and to emphasize the emerging role of semaglutide
in managing diabesity and non‑diabetic obesity.
2. GLP‑1‑biological effects and development of GLP‑1 RAs
Biological effects. GLP‑1 is an incretin hormone secreted in
a biphasic pattern by the neuroendocrine L cells in the distal
ileum and colon after consumption of nutrients, particu‑
larly glucose and other carbohydrates (11,12). It has a short
elimination half‑life (1‑2 min) due to proteolysis by dipeptidyl
peptidase IV and renal elimination (12). GLP‑1 receptors
are expressed in numerous organs, mainly occurring in the
pancreas, central nervous system (hypothalamus) and the
gastrointestinal tract, but also in the heart and kidneys (12).
GLP‑1 stimulates insulin secretion from the β‑pancreatic cells
in a glucose‑dependent manner, also promoting β‑pancreatic
cell survival and proliferation (13,14). Furthermore, GLP‑1
reduces glucagon secretion by α‑pancreatic cells through
complex endocrine mechanisms, which include somatostatin
stimulation and insulinotropic effects on the β‑pancreatic
cells (12). By slowing down gastric emptying, GLP‑1 further
reduces blood glucose and appetite (15). This effect on appetite
is not only attributed to the delayed gastric emptying but also
to its inuence on the hypothalamus as a neurotransmitter,
particularly on the lateral hypothalamus, and the paraventric‑
ular and arcuate nucleus (16,17). Other effects of endogenous
GLP‑1 include reduction in systolic blood pressure, increased
myocardial contraction, improved endothelial vasodilation,
increased glycogen storage, improved lipid prole, diuresis
and natriuresis induction (18‑21).
Development of GLP‑1 RAs. At present, six injectable (subcu‑
taneous) GLP‑1 RAs and one oral formulation are available in
Europe for T2DM treatment. Based on their pharmacological
properties, GLP‑1 RAs are classied into short‑ or long‑acting
agents. Short‑acting GLP‑1 RAs include exenatide stan‑
dard‑release (Byetta) and lixisenatide (Lyxumia). Their major
mechanism of action is based on slowing gastric emptying
and lowering postprandial glucose. Long‑acting GLP‑1 RAs
include exenatide modified‑release (Bydureon), liraglutide
(Victoza), dulaglutide (Trulicity) and semaglutide (Ozempic).
Compared to short‑acting compounds, long‑acting agents have
a mechanism of action that mainly comprises stimulating
insulin secretion and inhibiting glucagon release, thus inu‑
encing both postprandial and fasting glucose. The posology of
GLP‑1 RAs in T2DM is illustrated in Table I (22,23).
Liraglutide was the rst antidiabetic treatment approved
as a weight reduction drug in non‑diabetic obesity. Sold under
the name of Saxenda, liraglutide at a dose of 3.0 mg once daily
was approved by both Food and Drug Administration in 2014
and the European Medicines Agency in 2015 for long‑term
weight management (24).
3. Semaglutide in diabesity and non‑diabetic obesity
Excess weight, particularly when associated with visceral fat,
increases the risk of insulin resistance, metabolic syndrome
and T2DM (25,26). The link between excess weight and T2DM
supposably lies in the inflammatory state associated with
excess adipose tissue. Several pro‑inammatory mediators,
such as tumor necrosis factor‑α, interleukin‑6 and complement
component 3, along with fatty‑acid lipotoxicity inhibit intra‑
cellular insulin signaling, which may lead to pancreatic β‑cell
dysfunction and subsequently to T2DM (27). When a new
diagnosis of T2DM is made, it is crucial to educate the patient
regarding the importance of a healthy lifestyle, which includes
avoiding excess calories (particularly high‑glycemic‑index
carbohydrates) and increasing physical activity to prevent
cardiovascular and metabolic complications. Nicola et al (28)
noted a signicantly higher low‑density lipoprotein cholesterol,
hypertriglyceridemia, low high‑density lipoprotein cholesterol
and a higher prevalence of micro‑ and macroalbuminuria in
hypertensive diabetic patients.
The American Diabetes Association recommends
metformin as the first‑line drug for T2DM therapy, if not
contraindicated (10). GLP‑1 RAs are known to lower blood
glucose by stimulating insulin production in the pancreatic
β‑cells and inhibiting glucagon release by the pancreatic
α‑cells, combined with slowing gastric emptying and reducing
appetite and food consumption (29). Therefore, given their
beneficial effects on glucose metabolism and weight loss
potential, GLP‑1 RAs are currently recommended as a
second‑line therapy in T2DM. Furthermore, their action of
increasing insulin production and lowering glucagon action is
tailored in a glucose‑dependent manner, thus posing a low risk
of hypoglycemia and making them one of the most effective
and safe options when a more intensive antidiabetic treatment
is required (30).
Semaglutide (Ozempic) is a long‑acting GLP‑1 RA and
its administration is once‑weekly subcutaneously at doses of
0.5 and 1.0 mg, with 0.25 mg/week being the initiation dose
for the rst 4 weeks. The safety and efcacy of semaglutide
was investigated in the Semaglutide Unabated Sustainability
in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial
program. A summary of the major results from the SUSTAIN
clinical program is provided in Table II.
Semaglutide as a blood glucose‑lowering agent. SUSTAIN‑1
was a phase IIIa clinical trial that compared the safety and
efcacy of semaglutide (0.5 and 1.0 mg) over the course of
30 weeks vs. placebo in patients with T2DM that had no prior
drug therapy, only diet and exercise interventions. Compared to
the placebo, both doses of semaglutide produced a signicant
reduction in glycated hemoglobin (HbA1c) [‑1.45% with sema‑
glutide 0.5 mg vs. ‑1.55% with semaglutide 1.0 mg vs. ‑0.2%
with placebo; the estimated treatment difference (ETD) for
semaglutide 0.5 mg vs. placebo was ‑1.43% and the ETD for
semaglutide 1.0 mg vs. placebo was ‑1.53%; P for both doses
of semaglutide vs. placebo <0.0001] (31).
The SUSTAIN‑2 clinical trial compared semaglutide
0.5 and 1.0 mg with sitagliptin 100 mg over the course of
56 weeks in patients with T2DM inadequately controlled
with metformin, thiazolidinediones or both. HbA1c reduction
was greater with both doses of semaglutide vs. sitagliptin
(‑1.3% with 0.5 mg semaglutide vs. ‑1.6% with 1.0 mg sema‑
glutide vs. ‑0.5% with 100 mg of sitagliptin; ETD ‑0.77% with
semaglutide 0.5 mg and ‑1.06% with semaglutide 1.0 mg;
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 3
P for both doses of semaglutide vs. sitagliptin <0.0001 for
non‑inferiority and superiority) (32). Semaglutide 1.0 mg was
compared with once‑weekly exenatide in the SUSTAIN‑3
clinical trial, which was performed over the course of
56 weeks on 813 adults with T2DM on previous oral antidia‑
betic agents. A reduction in HbA1c of 1.5% with semaglutide
and 0.9% with exenatide was noted (ETD, 0.62%; P<0.0001
for noninferiority and superiority for semaglutide vs. exenatide
once‑weekly) (33).
SUSTAIN‑4 assessed the safety and efficacy of sema‑
glutide compared to insulin glargine in patients with T2DM
inadequately controlled with metformin (with or without
sulfonylureas). At week 30, semaglutide at 0.5 and 1.0 mg
achieved greater HbA1c reductions than insulin glargine
(1.21 vs. 1.64 vs. 0.83%; ETD, ‑0.38% with semaglutide 0.5 mg
and ‑0.81% with semaglutide 1.0 mg with ETD; P<0.0001 for
ETD for both doses of semaglutide vs. insulin glargine) (34).
In the SUSTAIN‑5 clinical trial, semaglutide was inves‑
tigated as an add‑on vs. placebo in patients with T2DM on
basal insulin, with or without metformin. At week 30, HbA1c
exhibited a signicant reduction of 1.4 and 1.8% with sema‑
glutide 0.5 and 1.0 mg, respectively, vs. 0.1% with placebo
(P for both doses of semaglutide vs. placebo <0.0001) (35).
The SUSTAIN‑7 clinical trial proved the superiority of
0.5 and 1.0 mg semaglutide in improving the mean HbA1c
when compared to dulaglutide 0.75 and 1.5 mg. Semaglutide
0.5 mg reduced the mean HbA1c by 1.5 vs. 1.1% with dulaglu‑
tide 0.75 mg. Furthermore, 1.0 mg of semaglutide produced
a reduction of 1.8% in HbA1c vs. 1.4% with dulaglutide
1.5 mg (36).
SUSTAIN‑8 compared once‑weekly semaglutide 1.0 mg
with once‑daily canagliozin 300 mg in patients with T2DM
inadequately controlled with metformin. Semaglutide was
superior to canagliozin in reducing HbA1c (ETD, ‑0.49%;
P<0.0001) (37). In SUSTAIN‑9, the efficacy and safety of
semaglutide were assessed when added to a sodium glucose
cotransporter‑2 (SGLT‑2) inhibitor in patients with T2DM
with poor glycemic control. Semaglutide in addition to a
SGLT‑2 inhibitor signicantly reduced HbA1c (ETD, ‑1.42%;
P<0.0001) compared with placebo. Semaglutide added
to a SGLT‑2 inhibitor was well tolerated with significant
improvements in glycemic control (38).
In SUSTAIN‑10, semaglutide (1.0 mg/week) was compared
with liraglutide (1.2 mg/day) in subjects with T2DM treated
with 1‑3 oral antidiabetic drugs. A total of 577 subjects were
randomized to receive either semaglutide or liraglutide.
Patients receiving semaglutide had a superior reduction
in HbA1c (ETD, ‑0.69%; P<0.0001). Both treatments had
similar safety profiles, with semaglutide having a higher
frequency of gastrointestinal reactions compared to liraglutide
(43.9 vs. 38.3%) (39).
Semaglutide and body weight reduction benets. In SUSTAIN‑1,
a marked body weight loss was observed with both doses of
semag lutide when c o m p a r e d to pl a c e b o. Sp e c i c a ll y, wi t h se m a ‑
glutide at 0.5 and 1.0 mg, a weight reduction of 3.73 and 4.53 kg
kg was achieved, respectively, while the placebo had an insig‑
nicant loss of 0.98 kg (ETD vs. placebo, ‑2.75 and ‑3.56 kg
with semaglutide 0.5 and 1.0 mg, respectively; P for both doses
of semaglutide vs. placebo <0.0001) (31). In SUSTAIN‑2,
at week 56, a weight loss of 4.3 kg with semaglutide 0.5 mg
and 6.1 kg with semaglutide 1.0 mg, and 1.9 kg with sitagliptin
100 mg was achieved (ETD, ‑2.35 kg with semaglutide 0.5 mg
and ‑4.20 kg with semaglutide 1.0 mg vs. sitagliptin; P for both
doses of semaglutide vs. sitagliptin <0.0001, with superiority of
sitagliptin) (32).
The SUSTAIN‑3 trial indicated that semaglutide‑treated
subjects achieved a greater weight reduction when compared
Table I. Posology of GLP‑1 RA in type 2 diabetes mellitus.
GLP‑1 RA Structure Posology
Exenatide standard‑release Exenatide‑4 derivative 5 µg twice daily for rst month, then increase to 10 µg twice daily, before
meals
Lixisenatide Exenatide‑4 derivative 10 µg once daily rst two weeks, then increase to 20 µg once daily,
before meals
Exenatide modied‑release Exenatide‑4 derivative 2 mg once weekly, with or without meals
Liraglutide Modied human GLP‑1 0.6 mg once daily for rst week, then increase to 1.2 mg once daily
(further increase up to 1.8 mg if poor glucose control), with or without
meals
Dulaglutide Modied human GLP‑1 0.75 mg once weekly in monotherapy (1.5 mg once weekly as add‑on
therapy), with or without meals
Semaglutide Modied human GLP‑1 0.25 mg once weekly for rst month, then increase to 0.5 mg once
weekly for at least one month (further increase up to 1 mg in case of
poor glycemic control), with or without meals
Semaglutide (oral) Modied human GLP‑1 3 mg once daily for one month, then increase to 7 mg once daily for at
least one month (further increase up to 14 mg in case of poor glycemic
control), before meals
GLP‑1 RA, glucagon‑like peptide 1 receptor agonist.
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
4
to exenatide‑treated subjects (‑5.6 vs. ‑1.9 kg; ETD ‑3.78 kg;
P<0.0001) (33). SUSTAIN‑4 compared semaglutide vs. insulin
glargine. Body weight loss was observed in semaglutide‑treated
subjects and at week 30, a loss of 3.5 kg with semaglutide 0.5 mg
and 5.2 kg with semaglutide 1.0 mg, compared to a weight gain
of 1.15 kg with insulin glargine was observed (34). This result
came with no surprise given the appetite‑reducing effects of
GLP‑1 and the anabolic effects of insulin. When added to basal
insulin, in patients with T2DM with or without metformin
treatment, semaglutide produced a signicant body weight
Table II. Summary of clinical trials from the SUSTAIN program.
Clinical trial Aim Main results
SUSTAIN‑1 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg signicantly reduced HbA1c vs. placebo
semaglutide vs. placebo in T2DM (‑1.45 vs. ‑1.55 vs. ‑0.2%); semaglutide 0.5 and 1.0 mg signicantly
patients without prior drug therapy reduced body weight vs. placebo (‑3.73 vs. ‑4.53 vs. ‑0.98 kg)
SUSTAIN‑2 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c
semaglutide vs. sitagliptin in T2DM reduction vs. sitagliptin 100 mg (‑1.3 vs. ‑1.6 vs. ‑0.5%);
patients with poor control on semaglutide 0.5 and 1.0 mg achieved a greater body weight
metformin, thiazolidinediones or both reduction vs. sitagliptin 100 mg (‑4.3 vs. ‑6.1 vs. ‑1.9 kg)
SUSTAIN‑3 To assess the safety and efcacy of Semaglutide 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. once‑weekly exenatide exenatide once weekly 2.0 mg (‑1.5 vs. ‑0.9%); semaglutide 1.0 mg
in T2DM patients on previous oral achieved a greater body weight reduction vs. exenatide once weekly
antidiabetic agents 2.0 mg (‑5.6 vs. ‑1.9 kg)
SUSTAIN‑4 To assess the safety and efcacy of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. insulin glargine in insulin glargine (‑1.21 vs. ‑1.64 vs. ‑0.83%); semaglutide 0.5 and 1.0 mg
T2DM patients with poor control on achieved a greater body weight reduction vs insulin glargine
metformin, with or without sulfonylureas (‑3.5 vs. ‑5.2 vs. +1.15 kg)
SUSTAIN‑5 To investigate the superiority of Semaglutide 0.5 and 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. placebo in T2DM placebo (‑1.4 vs. ‑1.8 vs. ‑0.1%); semaglutide 0.5 and 1.0 mg achieved
patients on basal insulin, with or without a greater body weight reduction vs. placebo (‑3.7 vs. ‑6.4 vs. ‑1.4 kg)
metformin
SUSTAIN‑6 To investigate the cardiovascular safety Semaglutide arm had a lower primary outcome (rst occurrence of
of semaglutide in T2DM cardiovascular death, nonfatal myocardial infarction or nonfatal
stroke) occurrence vs. placebo (6.6 vs. 8.9%); semaglutide arm had
lower rates of new or worsening nephropathy vs. placebo
(3.8 vs. 6.1%); semaglutide arm had a higher incidence of retinopathy
complications vs. placebo (3.0 vs. 1.8%)
SUSTAIN‑7 To assess the safety and efcacy of Semaglutide 0.5 mg achieved a greater HbA1c reduction vs.
semaglutide vs. dulaglutide in T2DM dulaglutide 0.75 mg (‑1.5 vs. ‑1.1%); semaglutide 1.0 mg achieved a
patients with poor control on metformin greater HbA1c reduction vs. dulaglutide 1.5 mg (‑1.8 vs. ‑1.4%);
semaglutide 0.5 mg achieved a greater weight reduction vs. dulaglutide
0.75 mg (‑4.6 vs. ‑2.3 kg); semaglutide 1.0 mg achieved a greater body
weight reduction vs. dulaglutide 1.5 mg (‑6.5 vs. ‑3.0 kg)
SUSTAIN‑8 To assess the safety and efcacy of Semaglutide 1.0 mg achieved a greater HbA1c reduction vs.
semaglutide vs. canagliozin in T2DM canagliozin 300 mg (‑1.5 vs. ‑1.0%); semaglutide 1.0 mg achieved a
patients with poor control on metformin greater body weight reduction vs. canagliozin 300 mg
(‑5.3 vs. ‑4.2 kg)
SUSTAIN‑9 To assess the safety and efcacy of Semaglutide markedly reduced HbA1c when added to a SGLT‑2
semaglutide when added to a SGLT‑2 inhibitor vs. placebo (‑1.5 vs. ‑0.1%); semaglutide markedly reduced
inhibitor in patients with poorly body weight when added to a SGLT‑2 inhibitor vs. placebo
controlled T2DM (‑4.7 vs. ‑0.9 kg)
SUSTAIN‑10 To assess the safety and efcacy of Semaglutide 1.0 mg had a greater HbA1c reduction vs. liraglutide
semaglutide vs. liraglutide in T2DM 1.2 mg (‑1.7 vs. ‑1.0%); semaglutide 1.0 mg had a greater body weight
patients on 1‑3 oral antidiabetic agents reduction vs. liraglutide 1.2 mg (‑5.8 vs. ‑1.9 kg)
T2DM, type 2 diabetes mellitus; HbA1c, glycated hemoglobin; SUSTAIN, Semaglutide Unabated Sustainability in Treatment of Type 2
Diabetes.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 5
reduction vs. placebo according to the results of SUSTAIN‑5
(‑3.7 kg with semaglutide 0.5 mg vs. ‑6.4 kg with semaglutide
1.0 mg vs. ‑1.4 kg with placebo; P for both doses of sema‑
glutide vs. placebo <0.0001) (35). In SUSTAIN‑7, semaglutide
was superior to dulaglutide regarding body weight reduction
properties. Semaglutide 0.5 mg achieved a weight reduction of
4.6 vs. 2.3 kg with dulaglutide 0.75 mg. Furthermore, an even
greater difference was observed between semaglutide 1.0 mg
vs. dulaglutide 1.5 mg (‑6.5 vs. ‑3.0 kg) (36).
Semaglutide was superior to canagliflozin in reducing
body weight (ETD, ‑1.06 kg; P<0.0029) in SUSTAIN‑8 (37).
A sub‑study of SUSTAIN‑8 compared the effects of sema‑
glutide 1.0 mg and once‑daily canagliozin 300 mg on body
composition in individuals with T2DM uncontrolled with
metformin. The results indicated no signicant differences
between semaglutide and canagliozin regarding changes in
body composition (40). In SUSTAIN‑9, adding semaglutide
to a SGLT‑2 inhibitor achieved signicant improvements in
body weight reduction compared to placebo (ETD, ‑3.81 kg;
P<0.0001) (38). Given the positive outcomes that were obtained
when adding semaglutide to canagliozin, it is indicated that
combining a GLP‑1 RA and a SGLT‑2 inhibitor may provide
an additive effect in improving glycemic control and body
weight reduction and also in reducing cardiovascular risk and
renal impairment.
Patients receiving semaglutide in SUSTAIN‑10 had
a superior reduction in body weight compared with the
liraglutide‑treated group (ETD, ‑3.83 kg; P<0.0001) (39).
Semaglutide was studied as a possible chronic weight
management drug in non‑diabetic obesity. A randomized,
double‑blinded, placebo‑controlled trial performed on
957 individuals without diabetes was performed to evaluate
the safety and efcacy of semaglutide in comparison with
liraglutide and placebo in promoting weight loss. Participants
received semaglutide at dosages ranging from 0.05 to 0.4 mg
or liraglutide 3.0 mg as once‑daily subcutaneous injections.
The estimated mean loss for the 0.4 mg semaglutide group
was ‑13.8 vs. ‑2.3% with placebo. Mean body weight reduc‑
tions with ≥0.2 mg semaglutide vs. liraglutide were signicant
(‑13.8 to ‑11.2 vs. ‑7.8%) (41). A double‑blinded randomized
clinical trial, which included 1,961 adults without T2DM with
a body mass index of at least 30 or at least 27 kg/m2 with
≥1 weight‑related coexisting comorbidity, investigated the role
of 2.4 mg subcutaneous semaglutide vs. placebo in addition
to lifestyle interventions. At week 68, the mean body weight
change was highly signicant in the semaglutide group vs.
the placebo group (‑14.9 vs. ‑2.4%; ETD, ‑12.4%; P<0.001).
A weight reduction of at least 5% was achieved by 86.4% of
the subjects in the semaglutide group vs. 31.5% in the placebo
group. A 10% weight reduction was achieved by 69.1% of
subjects in the semaglutide group vs. 12.0% of subjects in
the placebo group. A 15% weight reduction occurred in
50.5% of patients of the semaglutide group vs. 4.9% in the
placebo group (42). Given the proven benets of semaglutide
in managing chronic excess weight and its good safety prole,
the Food and Drug Administration recently approved the use
of semaglutide 2.4 mg/once‑weekly as an add‑on‑therapy to
lifestyle modications in adults with obesity or overweight
with at least one weight‑related comorbidity (43). Therefore,
semaglutide became the second GLP‑1 RA besides liraglutide
that may be used in managing non‑diabetic excess weight. The
Food and Drug Administration approval was based on the
results from the Semaglutide Treatment Effect in People with
Obesity (STEP) program, which consisted of four phase III
clinical trials. A summary of the STEP program is illustrated
in Table III (42,44‑46).
Oral semaglutide: Blood glucose and body weight benets.
Oral semaglutide (Rybelsus), the first oral GLP‑1 RA,
was studied in 10 phase IIIa clinical trials as part of the
PIONEER program. PIONEER‑1 was a 26‑week randomized,
double‑blinded clinical trial that compared the efcacy and
safety of oral semaglutide (3, 7 or 14 mg) as monotherapy
with placebo in subjects with T2DM managed by lifestyle
interventions. It was demonstrated that oral semaglutide at
all doses was superior to the placebo in improving HbA1c
(ranging from ‑0.6 to ‑1.1%) and in body weight reduction
(14 mg dose) (47). Results from PIONEER‑2 suggested that
oral semaglutide 14 mg was superior in reducing HbA1c
compared with empagliflozin 25 mg in a 52‑week trial
(1.3 vs. 0.9%; ETD ‑0.4%; P<0.0001). Furthermore, at week 52,
oral semaglutide achieved an average weight reduction of
4.7 vs. 3.8 kg with empagliozin, rendering oral semaglutide
signicantly more effective (P=0.0114) (48). The PIONEER‑4
clinical trial demonstrated that oral semaglutide (14 mg) was
non‑inferior in decreasing HbA1c to subcutaneous liraglutide
(1.8 mg) at week 26 (ETD, ‑0.1%; P<0.0001) and superior to
placebo (ETD, ‑1.1%; P<0.0001). Furthermore, oral semaglu‑
tide achieved a greater weight reduction than liraglutide and
placebo (‑4.4 vs. ‑3.1 vs. 0.5 kg; ETD, ‑1.2 kg vs. liraglutide
and ‑3.8 kg vs. placebo; P=0.0003 and P<0.0001, respec‑
tively) (49).
The PIONEER 10 clinical trial investigated the efcacy and
safety of oral semaglutide vs. dulaglutide in Japanese patients
with uncontrolled T2DM. Oral once‑daily semaglutide (14 mg)
achieved a signicant HbA1c reduction vs. once‑weekly dula‑
glutide (0.75 mg) (ETD, ‑0.3%; P=0.0170). Furthermore, oral
semaglutide signicantly reduced body weight vs. dulaglutide
(ETD, ‑2.6 kg for oral semaglutide 14 vs. 0.75 mg dulaglutide;
P<0.0 0 01) (50).
Cardiovascular benets of semaglutide. The SUSTAIN‑6 clin‑
ical trial investigated the cardiovascular safety of once‑weekly
subcutaneous administration of semaglutide. The primary
outcome composite (rst occurrence of cardiovascular death,
nonfatal myocardial infarction or nonfatal stroke) occurred in
6.6% in the semaglutide group vs. 8.9% in the placebo group
(P<0.0001 for noninferiority). Mortality rates from cardiovas‑
cular causes were similar among the studied groups, while
the semaglutide group had an advantage regarding lower rates
of new or worsening nephropathy [3.8 vs. 6.1%, hazard ratio
(HR)=0.64, P<0.01] (51). Furthermore, by improving glucose
metabolism, GLP‑1 RAs are able to prevent the development of
macroalbuminuria and also maintain an adequate glomerular
ltration rate, and are an efcient and safe option in diabetic
nephropathy (52). However, semaglutide‑treated subjects had
a higher incidence of retinopathy complications vs. placebo
(P=0.02) (51). Recently published results demonstrated that
semaglutide improved health‑related quality of life vs. placebo
in patients with T2DM with high cardiovascular risk in the
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
6
SUSTAIN‑6 trial, possibly explained by the reduction of
HbA1c and weight loss (53).
PIONEER‑6 investigated the cardiovascular outcomes for
oral semaglutide in subjects with T2DM and with high cardio‑
vascular risk in an event‑driven, randomized, double‑blinded,
placebo‑controlled trial. Oral semaglutide was non‑inferior to
placebo regarding cardiovascular safety, with major cardiovas‑
cular events occurring in 3.8% of the oral semaglutide‑treated
subjects vs. 4.8% in the placebo group (HR=0.79; P<0.001
for non‑inferiority) (54). The study did not have the statistical
power to demonstrate superiority, as it was an event‑driven
trial. Death from cardiovascular causes occurred in 0.9%
in the oral semaglutide group vs. 1.9% in the placebo group
(HR=0.49) and nonfatal myocardial infarction occurred in
2.3% in the oral semaglutide group vs. 1.9% in the placebo
group (HR=1.18), while nonfatal stroke occurred in 0.8% in
the oral semaglutide group vs. 1.0% in the placebo group
(HR=0.74). All‑cause mortality was encountered in 1.4% in
the oral semaglutide group vs. 2.8% in the placebo group
(HR=0.51) (54).
Semaglutide and nonalcoholic fatty liver disease (NAFLD).
NAFLD is a metabolic liver disease that has a broad spectrum
of clinical presentation, ranging from simple steatosis to severe
forms such as nonalcoholic steatohepatitis (NASH), cirrhosis
and hepatocellular carcinoma (55). Similar to that of T2DM
and obesity, the incidence of NAFLD is increasing worldwide.
It is estimated that up to 70‑80% of patients with T2DM and/or
obesity present with NAFLD (56,57). T2DM is an important
risk factor for the progression of NAFLD to more severe
forms (58‑60). The exact pathophysiological mechanisms
which lead to NAFLD remain to be completely elucidated,
but several proposed hypotheses include insulin resistance,
environmental factors, polymorphisms, adipose tissue
expandability and spleen mechanisms to promote liver fat
accumulation (61). Currently, lifestyle changes are the primary
tool in managing NAFLD, as to date, no pharmacological
treatment has been approved.
GLP‑1 RAs may be a potential therapeutic option given
their benets in T2DM and obesity, the two major drivers of
NAFLD (62). In a systematic review published in 2020 by
Lv et al (63), GLP‑1 RAs were determined to improve liver
enzymes and hepatic steatosis. A recently published meta‑
nalysis by Mantovani et al (64) investigated the published
data of placebo‑controlled, active‑controlled or randomized
controlled trials that evaluated the efficacy and safety of
GLP‑1 RAs in treating NAFLD or NASH in adults with or
without T2DM. They revealed GLP‑1 RAs to be efcient in
Table III. Summary of clinical trials from the STEP program.
Clinical trial Design Aim Main results
STEP‑1 68‑week randomized, To investigate the efcacy and safety of Semaglutide 2.4 mg achieved a weight
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. loss of 14.9 vs. 2.4% with placebo;
placebo‑controlled placebo in 1,961 adults with obesity or 86.4% of the semaglutide 2.4 mg group
overweight with comorbidities achieved a weight loss of ≥5 vs. 31.5%
with placebo
STEP‑2 68‑week randomized, To compare the efcacy and safety of Semaglutide 2.4 mg achieved a
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. weight loss of 9.6 vs. 7.0% with
placebo‑controlled semaglutide 1.0 mg/once‑weekly vs. semaglutide 1.0 mg vs. 3.4% with
placebo in 1,210 adults with T2DM and placebo; 68.8% of semaglutide
obesity or overweight with comorbidities 2.4 mg group achieved a weight loss
of ≥5 vs. 28.5% with placebo
STEP‑3 68‑week randomized, To investigate the efcacy and safety of Semaglutide 2.4 mg achieved a
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. weight loss of 16.0 vs. 5.7% with
placebo‑controlled placebo in combination with intensive placebo; 86.6% of semaglutide
behavioral treatment in 611 adults with 2.4 mg group achieved a weight loss
obesity or overweight with comorbidities of ≥5 vs. 47.6% with placebo
STEP‑4 68‑week randomized, To investigate the efcacy and safety of After 20 weeks run‑in, 803 adults
double‑blind, multicentre, semaglutide 2.4 mg/once‑weekly vs. reached the target dose of semaglutide
placebo‑controlled placebo in 902 adults with obesity or 2.4 mg and were randomized to
overweight continued treatment or placebo for
48 weeks; after 48 weeks, semaglutide
2.4 mg achieved an additional weight
loss of 7.9 vs. 6.9% with placebo; after
68 weeks, semaglutide 2.4 mg achieved
a total weight loss of 17.4%
T2DM, type 2 diabetes mellitus; STEP, Semaglutide Treatment Effect in People with Obesity.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 7
improving NAFLD, particularly liraglutide and semaglutide. A
randomized, double‑blinded, placebo‑controlled, phase 2 trial
compared daily semaglutide (0.1, 0.2 and 0.4 mg) with placebo
in patients with biopsy‑conrmed NASH. NASH resolution
without worsening of brosis was observed in 40% of cases in
the semaglutide 0.1 mg group, in 36% of cases in the semaglu‑
tide 0.2 mg group and in 59% in the semaglutide 0.4 mg group,
compared with 17% of cases in the placebo group (P<0.001,
semaglutide 0.4 mg vs. placebo). However, there was no
signicant improvement regarding the brosis stage between
semaglutide 0.4 mg and the placebo (P=0.48) (65).
4. Semaglutide‑side effects and cautions
Semaglutide mainly shares the classically observed side
effects of other GLP‑1 RAs (Fig. 1).
Gastrointestinal side effects. The common side effects associ‑
ated with GLP‑1 RAs use are gastrointestinal reactions, mainly
nausea, vomiting and diarrhea. During the SUSTAIN program
that assessed safety parameters, the rate of discontinuation due
to adverse events was low (5‑13%), with SUSTAIN‑6 reporting
a higher discontinuation rate (almost 20%). The major
reasons for the discontinuation were gastrointestinal adverse
events (31‑36). Nausea occurred in 17.0%, diarrhea in 12.2%
and vomiting in 6.4% of patients treated with semaglutide
0.5 mg. As for patients treated with semaglutide 1.0 mg, nausea
occurred in 19.9%, diarrhea in 13.3% and vomiting in 8.4% of
cases (66,67). Semaglutide has a similar gastrointestinal safety
prole as other GLP‑1 Ras (68,69). A metanalysis from 2018
that included nine phase III randomized controlled trials and
9,773 subjects highlighted that semaglutide did not increase the
risk of any adverse events, hypoglycemia or pancreatitis, but
had a higher risk of gastrointestinal reactions (mainly nausea,
vomiting, diarrhea, abdominal discomfort and decreased appe‑
tite) when compared to other therapies [relative risk (RR)=1.98;
P<0.001] (70). Given that the occurrence of gastrointestinal
reactions is the main reason for treatment discontinuation, a
titration regimen is recommended for semaglutide, starting
with 0.25 mg once‑weekly for 4 weeks, increasing the dose
to 0.5 mg once‑weekly for at least 4 weeks. If a higher dose is
required to achieve proper glycemic control, the dose may then
be increased to 1.0 mg once‑weekly, assuming the tolerance
is adequate. For oral semaglutide, the initial dose is 3 mg/day
for the first month, then the dose should be increased to
7 mg/day for at least another month (the dose may be increased
up to 14 mg/day in the case of poor glycemic control).
Risk of hypoglycemia. The frequency of hypoglycemia was
observed to be usually low (1‑2%) when semaglutide was
not combined with insulin or sulphonylureas (31,32,36,71).
However, when added to sulphonylureas or insulin, hypogly‑
cemia had higher frequencies (4‑10%) (33‑35,71). Shi et al (70)
observed no increased risk of hypoglycemia with semaglutide
when compared to other therapies (RR=1.07; P=0.317).
Medullary thyroid carcinoma and pancreatitis concerns.
Rodent studies have indicated an increased risk of devel‑
oping medullary thyroid carcinoma following treatment
with GLP‑1 RAs, but without existing conrmation of these
results in humans (72,73). The SUSTAIN program suggested
no elevation in calcitonin levels. However, GLP‑1 RAs should
Figure 1. Side effects, cautions and concerns related to GLP‑1 RAs. GLP‑1 RAs, glucagon‑like peptide 1 receptor agonists.
TILINCA et al: SEMAGLUTIDE IN DIABESITY APPROACH
8
not be used in individuals with a personal or family history of
medullary thyroid carcinoma or multiple endocrine neoplasia
type 2A and 2B (23,74). Concerns about pancreatitis in
incretin‑based therapy have been raised due to mild elevations
in amylase and/or lipase levels (75). The risk of pancreatitis
with semaglutide was not signicantly higher when compared
with other therapies (0.3 vs. 0.4%, RR=0.82; P=0.641) (70).
In 2020, Abd El Aziz et al (76) published a metanalysis based
on cardiovascular outcome trials and indicated no signicant
risk of acute pancreatitis or any malignant disease.
Ocular and renal effects. SUSTAIN‑6 noted an increased
risk of retinopathy complications (vitreous hemorrhage,
blindness or conditions requiring treatment with an intra‑
vitreal agent or photocoagulation) in the semaglutide group
vs. the placebo group (3.0 vs. 1.8%, HR=1.76, P=0.02) (51).
On the contrary, SUSTAIN‑1‑5 and ‑7 did not report any
similar results. One explanation for these observations may
be the HbA1c levels at baseline and the rapidity of reduction
of HbA1c, considering that rapid improvement in glucose
control has been associated with aggravated diabetic reti‑
nopathy (77‑79). No dose adjustment is required based on age
or in patients with mild, moderate or severe renal or hepatic
impairment; however, it is not recommended in patients with
end‑stage kidney disease and experience in severe hepatic
disease is limited (66,67).
5. Future considerations
Weight loss induced by GLP‑1 RAs is usually observed after
long‑term treatment. GLP‑1 RAs promote weight loss mainly
by reducing appetite, thus reducing food consumption and
by increasing satiety. Treatment adherence is important,
as well as lifestyle changes, which include dietary caloric
decit and increased physical activity. It was observed that
a higher dose of GLP‑1 RA is associated with a higher
chance to obtain a higher weight reduction. However, weight
reduction usually lasts as long as the treatment is continued,
with near‑baseline weight values returning within months of
discontinuation of pharmacological treatment as reported by
Kelly et al (80).
Semaglutide is the second GLP‑1 RA that may be safely
and efciently used in non‑diabetic individuals with excess
weight, providing a new milestone in the pharmacological
treatment of obesity. Furthermore, oral semaglutide, given
its posology, may provide higher attractiveness and better
treatment adherence, and thus, future research into the use of
oral semaglutide in non‑diabetic obese patients may provide
novel insight and an effective and safe weight‑loss method.
Combination therapy with semaglutide is also being studied.
A randomized, placebo‑controlled, multiple ascending dose,
phase Ib trial investigated the combination of semaglutide
2.4 mg with cagrilintide, a long‑acting amylin analogue.
Concomitant treatment with cagrilintide and semaglutide
was well tolerated and produced a greater weight loss than
semaglutide alone (81). Further studies are required to assess
variable combination options with semaglutide to provide
novel treatments for long‑term weight management.
The cardiovascular safety of semaglutide was assessed
in SUSTAIN‑6 for once‑weekly subcutaneous formulation
and in PIONEER‑6 for the oral formulation, as discussed
previously. A Heart Disease Study of Semaglutide in Patients
with Type 2 Diabetes (SOUL) will bring additional data
regarding the cardiovascular outcomes with oral semaglutide
vs. placebo (82,83). Semaglutide, as with other agents from
the GLP‑1 RAs drug class, reduces the risk of cardiovas‑
cular events in high‑risk patients. The American Diabetes
Association currently recommends the use of GLP‑1 RAs as
part of the antidiabetic treatment in patients with T2DM with
atherosclerotic cardiovascular disease or established kidney
disease (10). The positive effects of GLP‑1 RAs on cardiovas‑
cular function may be explained by the benecial effects of
this drug class on glucose metabolism, body weight and blood
pressure. The exact mechanisms of how GLP‑1 RAs provide
cardiovascular benefits remain to be elucidated in future
research. Furthermore, long‑term studies are required to inves‑
tigate the potential additive effects on the cardiovascular and
renal function of the combination between a GLP‑1 RA and an
SG LT‑2 i n h ibi tor.
Semaglutide achieved promising results in improving
NAFLD. Larger randomized clinical trials are required to
conrm its applicability in NAFLD. Furthermore, clinicians
should focus on preventing the development of NAFLD by
promoting a healthy lifestyle, particularly in individuals
suffering from T2DM and obesity who are at high risk of
developing steatohepatitis.
6. Conclusions
The present review highlighted the benets of semaglutide not
only as an antidiabetic agent but also as a drug with effective
weight reduction properties. Clinicians should be aware that
semaglutide therapy is one of the most modern methods of
treatment for patients with T2DM and obesity, and has recently
been approved for the treatment of non‑diabetic excess weight.
Semaglutide (both subcutaneous and oral formulation) is an
efcient and safe therapeutic approach for diabesity, with an
excellent cardiovascular prole. Regarding the microvascular
complications, potential for reducing diabetic nephropathy
was noted, with concerns regarding a possible worsening of
diabetic retinopathy, thus requiring further studies for clari‑
cation. The perspective of oral semaglutide as an antiobesity
drug is promising and may be associated with increased treat‑
ment adherence. There is still increased potential for further
research to enhance and optimize the use of semaglutide in
diabesity and non‑diabetic obesity to reduce morbidity and
mortality associated with these metabolic disorders and to
improve quality of life.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
Not applicable.
EXPERI MENTAL AND THER APEUTIC MEDICINE 22: 1167, 2021 9
Authors' contributions
MCT and RAT contributed to the design and conception of
the study. RAT and CN searched and consulted the relevant
literature, selected the studies/data and wrote the rst draft of
the manuscript. MCT, AV and IT substantially added contribu‑
tions by revising and editing the nal manuscript. All authors
have read and approved the nal version of the manuscript.
Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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